Hong Kong Guide to Good Manufacturing Practice for the ... · Products. The PIC/S Guide to Good Manufacturing Practice for Medicinal Products would be the standard used during the

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Hong Kong Guide to

Good Manufacturing Practice for the Secondary Packaging of Pharmaceutical Products Version 1.3

Drug Office, Department of Health

Hong Kong Guide to Good Manufacturing Practice for the Secondary Packaging of Pharmaceutical Products Page 2

Contents list

1. QUALITY MANAGEMENT............................................................................................. 4

2. PERSONNEL................................................................................................................ 4

3. PREMISES .................................................................................................................. 6

4. MATERIALS CONTROL................................................................................................ 7

5. GOOD PRACTICES IN SECONDARY PACKAGING ........................................................ 8

6. QUALITY CONTROL .................................................................................................... 9

7. DOCUMENTATION.................................................................................................... 10

8. STOCK HANDLING AND STOCK CONTROL................................................................ 12

9. REJECTED AND RETURNED GOODS.......................................................................... 12

10. PRODUCT COMPLAINTS ........................................................................................... 13

11. PRODUCT RECALL .................................................................................................... 13

12. SELF INSPECTION.................................................................................................... 14

13. CONTRACT PACKAGING OR ANALYSIS ARRANGEMENTS......................................... 14


PURPOSE OF THIS GUIDANCE

This document serves to provide guidance to companies conducting secondary packaging but it is not meant to replace the PIC/S Guide to Good Manufacturing Practice for Medicinal Products. The PIC/S Guide to Good Manufacturing Practice for Medicinal Products would be the standard used during the GMP inspection of all manufacturers (including secondary packaging manufacturers) of pharmaceutical products.

DEFINITION

Secondary packaging is a manufacturing step and means the labelling, relabelling, cartoning, re-cartoning or adding additional information (including inserts) to pharmaceutical products which are already enclosed in the container in which they are to be sold or supplied.

SCOPE

This document applies to any company carrying out the secondary packaging of pharmaceutical products in Hong Kong.

Secondary packaging operations involving the application of a supplementary label that does not obliterate, change or display information relating to the original name, list of ingredients, dosage instructions, batch number or expiry date of the pharmaceutical product are exempted from the requirements of this Good Manufacturing Practice (GMP) Guide.

Full compliance with the Hong Kong GMP Guidelines for Pharmaceutical Products applies to packaging of a bulk product to become a finished product which involves the use of primary packaging materials. Primary packaging materials are packaging materials that are intended to be in direct contact with the products.


1. QUALITY MANAGEMENT

1.1 Companies carrying out secondary packaging of pharmaceutical products should establish and maintain a Quality System setting out responsibilities, organisational structure, resources, processes, procedures and other activities necessary to ensure confidence in the quality of the products released for supply after secondary packaging.

1.2 The Quality System should be fully documented and its effectiveness monitored on a regular basis. All Quality System related activities should be defined and documented. A Quality Manual or equivalent documentation approach should be established and maintained.

1.3 Management should appoint a Quality Assurance Officer who should have defined responsibilities for ensuring that a Quality System is implemented and maintained.

1.4 A system should be established and maintained to approve suppliers of packaging materials to be used in secondary packaging. In the case of critical materials such as printed packaging materials, the reliability of the suppliers may need to be verified by the Quality Assurance Officer conducting on-site audits.

1.5 The Quality System should ensure that:

a. Management responsibilities are clearly defined.

b. A system of change control is in place to document and manage any changes that

may impact the quality of the final product.

c. Appropriate corrective and preventative actions (commonly known as CAPA) are

taken (and documented) to correct deviations and prevent their re-occurrence.

2. PERSONNEL

Key Personnel

2.1 Key personnel include Person in charge of secondary packaging and Quality Assurance Officer. They must be independent from each other. There should be a staff organisation chart showing this independence.

2.2 The company should appoint a Person in charge of secondary packaging to be responsible for the following activities:

a. Establish and maintain the company’s Quality System, and coordinate regular

reviews of the effectiveness of the Quality System.

b. Supervise the secondary packaging operations.

c. Ensure that products are packaged and stored according to the appropriate

documentation in order to obtain the required quality.

d. Approval of documentation and procedures relating to secondary packaging

operations.

e. Check the maintenance of premises and equipment.

f. Coordination of self-inspections.

g. Ensure that the required training of his department personnel is carried out and

adapted according to need.

2.3 The company should also appoint a Quality Assurance Officer to be responsible for the following activities:

a. Establish and maintain the company’s Quality System, and coordinate regular

reviews of the effectiveness of the Quality System.


b. Approval of products received for secondary packaging.

c. Approval of packaging materials, including printed packaging materials, before they

are used in secondary packaging operations.

d. Approval of documentation and procedures relating to quality control.

e. Certification that each batch of pharmaceutical product that is subject to secondary

packaging has been processed and controlled in accordance with the requirements

set out in this guidance document before the batch is released for sale or supply.

f. Establish and maintain a list of approved suppliers of packaging materials, including

printed packaging materials, to be used in secondary packaging operations.

g. Coordination of self-inspections.

h. Coordination of the handling of complaints and recalls.

i. Approval of contract agreements.

j. Ensure that the required training of his department personnel is carried out and

adapted according to need.

Qualifications of Key Personnel

2.4 The Person in charge of secondary packaging operations should have adequate academic qualification, sufficient experience in pharmaceutical manufacture and/or secondary packaging, and necessary knowledge in the principle of GMP, to enable an understanding of the risks associated with the activities being undertaken and the regulatory environment.

2.5 The Quality Assurance Officer should have adequate academic qualification and the necessary knowledge in the principles of GMP and legislation related to pharmaceutical products. This person should have sufficient experience in secondary packaging of pharmaceutical products and should have a clear understanding of the risks associated with the activities being undertaken in the regulatory environment.

Training

2.6 Adequate training should be provided for all personnel whose activities could affect the quality of the final products. Training programs should be available and its practical effectiveness should be periodically assessed. Records of training provided to personnel should be maintained.

Personal Hygiene

2.7 Every person entering the secondary packaging area(s) should wear protective garments appropriate to the operations to be carried out which includes at least a hair cover and clean protective garments.

2.8 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the packaging and storage areas should be prohibited. In general, any unhygienic practice within the packaging areas or in any other area where the product might be adversely affected should be forbidden.

2.9 Visitors or untrained personnel should, preferably, not be taken into the secondary packaging area(s). If this is unavoidable, they should be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They should be closely supervised.


3. PREMISES

3.1 Premises used for secondary packaging should be specifically designed, constructed and laid out to avoid product mix-up and cross-contamination.

3.2 The size of the secondary packaging area(s) should reflect the volume of work involved. The adequacy of the working space or work bench for secondary packaging should permit the orderly and logical positioning of equipment and materials so as to avoid confusion and to minimize the risk of mix-up between different pharmaceutical products and their components.

3.3 Secondary packaging areas and associated storage areas should be well-lit and effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled and to the operations undertaken within them. Temperature and humidity should be monitored regularly, and record made in a logbook.

3.4 There should be adequate storage areas with general good housekeeping. The storage areas should be designed and equipped to prevent the entry of insects, rodents and other animals.

3.5 There should be a pest control program to control the entry of insects, rodents and other animals. Appropriate records should be kept.

3.6 Segregated areas should be provided for the storage of approved, quarantined, rejected, recalled and returned materials or products.

3.7 Rest and refreshment rooms should be separate from the secondary packaging area(s).

3.8 Adequate toilet facilities should be available and should be kept clean and in good order. Toilets should not open directly into the secondary packaging area(s).

3.9 Premises should be cleaned and, where applicable, disinfected according to detailed written procedures. Appropriate records should be kept.


4. MATERIALS CONTROL

Products subject to Secondary Packaging

4.1 For each delivery of pharmaceutical product received for secondary packaging, the containers should be checked for identity, integrity of package and seal, and correspondence between the delivery note and the supplier’s labels, and for compliance with product quality specifications.

4.2 Pharmaceutical products held in the storage area should be appropriately labelled. There should be appropriate procedures or measures to assure the identity of the contents of each container of the products.

4.3 All pharmaceutical products should be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation.

4.4 Those products requiring special storage conditions (for example specific temperature and humidity conditions) should be placed in separate areas constructed and equipped to provide the specified conditions. The storage conditions should be continuously monitored and recorded.

Packaging Materials

4.5 Materials to be used in secondary packaging, including printed packaging materials, should only be obtained from approved suppliers named in the relevant specification for that material.

4.6 Each delivery or batch of labels and printed packaging materials received should be examined and approved by the Quality Assurance Officer, and given a specific reference number for traceability purposes. Only starting materials which have been released by the Quality Assurance Officer should be used.

4.7 Particular attention should be given to the handling and control of labels and printed packaging materials, including the need for them to be:

a. Purchased from approved suppliers named in the relevant specification.

b. Stored in adequately secure conditions such as to exclude unauthorized access.

c. Stored in separate, closed containers so as to avoid mix-ups.

d. Issued for use only by authorized personnel following an approved and documented

procedure.

e. Transported to the secondary packaging area in separate, closed containers so as to

avoid mix-ups.

4.8 Out-dated or obsolete printed packaging material should be destroyed and their disposal recorded.

5. GOOD PRACTICES IN SECONDARY PACKAGING

5.1 The appropriate registered particulars of the pharmaceutical products that are subject to secondary packaging should be complied with and, where necessary, the approval of the holder of the Certificate of Drug/Product Registration should be sought if there is any variation to the registered particulars.

5.2 When setting up a program for the secondary packaging operations, particular attention should be given to minimizing the risk of cross-contamination, mix-ups or substitutions. The secondary packaging of different products should not be carried out in close proximity unless there is physical segregation.

5.3 Special care should be taken when using cut-labels and when over-printing is carried out off-line. Roll-feed labels are preferable to cut-labels in helping to avoid mix-ups.

5.4 Written procedures should be available for the handling of any spillage or breakage involving pharmaceutical products containing highly active substances (e.g. cytotoxics, steroids, hormones, etc.) or highly sensitising substances (e.g. penicillins, cephalosporins, etc.).

5.5 All products and materials used for secondary packaging operations should be checked before use by a designated person for quantity, identity and conformity with the Packaging Instructions.

5.6 Line clearance checks should be performed prior to commencement of each secondary packaging operation. Steps should be taken to ensure that the working area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation.

5.7 Each batch of product produced must be assigned a unique batch number which may incorporate the original manufacturer’s batch number and a suffix to identify each separate packaging run. Alternative batch numbering systems that provide full traceability to each packaging run may be accepted.

5.8 The correct performance of any printing operation (for example batch number coding and expiry dating) should be checked and recorded. Attention should be paid to printing by hand which should be re-checked at regular intervals.

5.9 Printed and embossed information on packaging materials should be distinct and resistant to fading or erasing.

5.10 On-line control of the product during secondary packaging should, where applicable, include checking the following:

a. General appearance of packages.

b. Completeness of packages.

c. Correctness of products and packaging materials used.

d. Correctness of over-printing, e.g. batch number, expiry date.

e. Correctness of supplementary labels applied to products.

5.11 Any deviation from instructions or procedures should be avoided as far as possible. If a deviation occurs, it should be approved in writing by the Quality Assurance Officer.

5.12 Any significant or unusual discrepancy observed during reconciliation of the amount of printed packaging materials used and the number of units produced should be investigated and satisfactorily accounted for before release for sale or supply.

5.13 Upon completion of a secondary packaging operation, any unused batch-coded packaging materials should be destroyed and their destruction recorded. A documented procedure should be followed if un-coded printed materials are returned to stock.



5.14 Finished products should be held under quarantine and stored under suitable conditions until their final release.

6. QUALITY CONTROL

6.1 There should be a designated and independent person in charge of Quality Control (QC). This may be the Quality Assurance Officer or another, independent person.

6.2 The identity, authenticity and quality of each batch of pharmaceutical product that is to be the subject of secondary packaging should be verified upon receipt by visual examination of the products and check against documentation such as delivery notes, certificates of analysis, established specifications, as well as the integrity of packaging/seals. These checks should be documented.

6.3 If a valid certificate of analysis is not available for a batch of pharmaceutical product, it should be tested for compliance with established specifications by an appropriately accredited laboratory before it is approved for secondary packaging.

6.4 Where unlabelled containers of pharmaceutical products are received for secondary packaging, the identity of each batch should be verified by representative samples tested by an appropriately accredited laboratory using specific chemical or instrumental techniques (irrespective of the availability of a certificate of analysis for the batch). Furthermore, unlabelled containers of pharmaceutical products should be subject to secondary packaging in a single packaging run to minimise the risk of mix-up of remaining unlabelled containers.

6.5 The identity and quality of packaging materials to be used in secondary packaging, including printed packaging materials, should be verified against established specifications. These checks should be documented.

6.6 Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of packaging documentation, compliance with finished product specification and examination of the final finished pack.

6.7 Reference samples should be representative of the batch of materials or products from which they are taken and should be of a size sufficient to permit at least a full re-examination.

6.8 Reference sample and/or retention samples from each batch of finished products should be retained till one year after the expiry date. Finished product retention samples should be kept in their final packaging and stored under the recommended conditions. Where a batch is packaged in two, or more, distinct packaging operations, at least one retention sample should be taken from each individual secondary packaging operation.

6.9 Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.


7. DOCUMENTATION

General Requirements

7.1 Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant statutory requirements for licensed manufacturers and holders of the Certificate of Drug/Product Registration.

7.2 Documents should be approved, signed and dated by appropriate and authorised persons.

7.3 Documents should have unambiguous contents; title, nature and the purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

7.4 Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.

7.5 Documents should not be hand-written; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.

7.6 Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.

7.7 The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the packaging of pharmaceutical products are traceable.

7.8 Batch documentation must be kept for one year after the expiry of the batch to which it relates or at least five years after certification of the batch by the Quality Assurance Officer, whichever is the longer.

7.9 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorised persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention.

Secondary Packaging Documents

7.10 All packaging materials used in secondary packaging operations should have approved specifications which serve as the basis for quality evaluation by the Quality Assurance Officer upon their receipt.

7.11 Written receipt, release and rejection procedures should be available for materials and products, and in particular for the release for sale or supply of the finished product by the Quality Assurance Officer. Records of receipt, release and rejection should be maintained for materials and products.


Packaging Instructions

7.12 There should be formally authorised Packaging Instructions for each product, pack size and type. These should normally include, or have a reference to, the following:

a. name of the product;

b. description of its pharmaceutical form, and strength where applicable;

c. the pack size expressed in terms of the number, weight or volume of the product in

the final container;

d. a complete list of all the packaging materials required, including quantities, sizes

and types, with the code or reference number relating to the specifications of each

packaging material;

e. where appropriate, an example or reproduction of the relevant printed packaging

materials, and specimens indicating where to apply batch number references, and

shelf-life of the product;

f. checks that the equipment and work station are clear of previous products,

documents or materials not required for the planned packaging operations (line

clearance), and that equipment is clean and suitable for use;

g. special precautions to be observed, including a careful examination of the area and

equipment in order to ascertain the line clearance before operations begin;

h. a description of the packaging operation, including any significant subsidiary

operations, and equipment to be used; and

i. details of in-process controls with instructions for sampling and acceptance limits.

Batch Packaging Records

7.13 A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions.

The batch packaging record should contain the following information:

a. the name and batch number of the product;

b. the date(s) and times of the packaging operations;

c. identification (initials) of the operator(s) who performed each significant step of the

process and, where appropriate, the name of any person who checked these

operations;

d. records of checks for identity and conformity with the Packaging Instructions

including the results of in-process controls;

e. details of the packaging operations carried out, including references to equipment

and the packaging lines used;

f. samples of printed packaging materials used, including specimens of the batch

coding, expiry dating and any additional overprinting;

g. notes on any special problems or unusual events including details, with signed

authorisation for any deviation from the Packaging Instructions;

h. the quantities and reference number or identification of all printed packaging

materials and bulk product issued, used, destroyed or returned to stock and the

quantities of obtained product, in order to provide for an adequate reconciliation.

Where there are robust electronic controls in place during packaging there may be

justification for not including this information;

i. approval by the person responsible for the packaging operations.


8. STOCK HANDLING AND STOCK CONTROL

Stock Rotation and Control

8.1 Comprehensive records should be maintained showing all receipt and issue of products (for secondary packaging) according to batch number.

8.2 Periodic stock reconciliation should be performed comparing the actual and recorded stocks. In any event, this should be performed when each batch is totally used up. All significant stock discrepancies should be subjected to investigation as a check against inadvertent mix-ups and wrong issues.

8.3 The issue of products for secondary packaging should normally observe the principle of stock rotation, i.e. first-in-first-out.

8.4 Products with broken seals, damaged packaging or suspected of possible contamination must not be sold or supplied.

8.5 Goods bearing an expiry date must not be received or supplied after their expiry date or so close to their expiry date that this date is likely to occur before the goods are used by the customer.

8.6 All labels and containers of products should not be altered, tampered or changed. The legislative requirements relating to labels and containers for pharmaceutical products should be complied with at all times.

Delivery of Finished Products

8.7 Before delivery, each consignment should be checked against the relevant documentation and physically verified by label description, type and quantity, against the order.

8.8 Records should be maintained of the distribution of each batch of the product packaged in order to facilitate the recall of the batch if necessary.

9. REJECTED AND RETURNED GOODS

Rejected Goods

9.1 Rejected materials and products should be clearly marked as being rejected and stored separately in a locked area with restricted access. They should be either returned to the suppliers or destroyed. Whatever action is taken should be recorded and approved by the Quality Assurance Officer.

9.2 All pharmaceutical products must be destroyed or disposed of in accordance with the provisions of the relevant legislative requirements.

Returned Goods

9.3 There should be a Standard Operating Procedure (SOP) for the handling of returned products. Records of all returns goods should be kept.

9.4 All returned products should be kept apart from saleable stock until a decision has been reached regarding their disposal.

9.5 Products should only be returned to saleable stock if:

a. The goods are in their original unopened containers and in good condition;

b. It is known that the goods have been stored and handled under proper conditions;

c. The remaining shelf life period is acceptable; and


d. The goods have been examined and assessed by the Quality Assurance Officer. This

assessment should take into account the nature of the product, any special storage

conditions required, and the time which had elapsed since it was distributed. Special

attention should be given to thermo-labile products.

9.6 The returned products should be formally released to the saleable stock by the Quality Assurance Officer.

10. PRODUCT COMPLAINTS

10.1 An SOP describing the actions to be taken for the handling of all written and oral complaints regarding a product should be available. The SOP should ensure that the complaints received are investigated and followed through, that corrective actions are taken to prevent repeated complaints, and, where a decision is made to recall the product, the details of the recall.

10.2 There should be a record for each individual complaint.

Investigations

10.3 The Quality Assurance Officer should initiate the investigation immediately and all investigation should be documented in writing. The investigation should take into consideration the condition and circumstances under which the product was distributed, stored and used.

10.4 If a product defect is discovered or suspected in a batch, consideration should be given to determine whether other batches are also affected.

10.5 An investigation report should be prepared with all corrective/preventive actions clearly stated.

11. PRODUCT RECALL

11.1 There should be an SOP for all urgent and non-urgent product recalls.

11.2 In the event of a recall, all customers to whom the product has been distributed should be informed with the appropriate degree of urgency.

11.3 The recall message should indicate whether the recall needs to be carried out at the retail level, and whether there is a need to remove all recalled products immediately from the shelves, and prevent their mixing with other saleable stocks.

11.4 If the product is exported, the overseas counterparts and/or regulatory authorities must be informed of the recall.

11.5 All actions taken in connection with the recall must be approved by the company and/or regulatory authorities, and recorded.


12. SELF INSPECTION

12.1 Self inspections should be conducted in order to monitor the implementation and compliance with the requirements of this Guidance Document and to propose necessary corrective measures.

12.2 Personnel matters, premises, equipment, documentation, assembly, quality control, distribution of the pharmaceutical products, arrangements for dealing with complaints and recalls should be examined at intervals following a pre-arranged program.

12.3 Self inspections should be conducted in an independent and detailed way by designated competent persons. Independent audits by external experts may also be useful.

12.4 All self-inspections should be recorded. Reports should contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken should also be recorded.

13. CONTRACT PACKAGING OR ANALYSIS ARRANGEMENTS

13.1 Where secondary packaging or analysis of pharmaceutical products is carried out under contract, a written contract agreement between the Contract Giver and the Contract Receiver should be available to describe the arrangements and responsibilities of both parties.

13.2 The arrangements and responsibilities for any contracted activities should be consistent with the requirements of Chapter 7 of the PIC/S GMP Guide.