Paul Valéry -

Nallianco LLC, New Vernon, New Jersey, U.S.A.

Michael D. Karaim

Brewster, Massachusetts, U.S.A.

§211.100 WRITTEN PROCEDURES; DEVIATIONS

(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.

These two subsections embody the basic underlying concept of current good manufacturing practice (CGMP): there shall be adequate written procedures that have been approved by responsible persons, and for which there is documentation that the procedures have been followed.

The drafting and approval of important procedures such as these cannot be left to chance. Written standard operating procedures (SOPs) define how things are to be done and provide a basis for the training of new or relocated personnel. SOPs are a fundamental extension of the CGMPs—the latter ideally should define what is to be achieved, whereas the SOPs provide company-specific approaches on how to meet these requirements. There should be a master SOP, which describes the overall procedure (SOP on SOPs). This procedure defines how to initiate/revise an SOP, format, who should review and approve (with defined areas of responsibility), frequency of routine review (often every two years), mechanism of issue and replacement of outdated versions, training, archiving, and destruction. Document control is essential for the SOP system (and all manufacturing and control documents). The life cycle of a document (creation, distribution, use, archiving, and destruction) must be considered in estab- lishing the control system. Many firms now use automated document systems that provide a higher level of document control in the review, approval, and distribution processes. For example, current versions of SOPs are available electronically for review at designated terminals and only to trained and qualified personnel. Hard copy printouts are date stamped and accompanied by a statement such as copy only valid for XX/XX/XX (that day only). Manual or paper systems are also common and can be very effective. However, version and distribution control (especially forms and attachments) can provide additional challenges. The SOP supplier [Usually Quality Assurance (QA)] should ideally issue numbered copies to identified recipients and copying of distributed SOPs should not be permitted; this can be monitored by printing the number (or other confirmation) in a different color so that photocopying would be obvious. The

use of paper stock with different colors, borders, or unique markings is another way of assuring original distribution and avoiding/prohibiting photocopying.

Many SOP systems are a combination of electronic and paper system and require both elec- tronic and paper controls (numbering system, version control and incrementing, referencing related documents, distribution control of draft and official document copies, and change control). It is important to note that any process or system that does not work in a manual (paper) system will probably also fail in an electronic system.

A typical SOP format includes sections for the following:

B Purpose and Scope

B Definitions

B Equipment/Materials/Supplies and Precautions

B Responsibilities

B Procedure (work process)

B References and Linkages (other related procedures/systems)

B Attachments (forms)

B Change History

SOPs are usually written by department and function (e.g., Manufacturing, Packaging, QA) and describe work activities, parts of systems, or in some cases a complete departmental system. This approach is somewhat limited when considering quality systems that cross multiple depart- ments [e.g., investigations, corrective/preventive action (CAPA), Change Control, Annual Product Review, Validation, Technology Transfer, etc.]. Multi- or cross-functional SOPs are often needed to define the system or work process. Refer to chapter 14 on quality systems approach.

Considerations for designing and implementing effective SOPs and sustainable systems include the following.

Design and Definition Elements

B Logical/understandable flow of inputs, activities, and outputs.

B Language and/or reading level appropriate to the user.

B Clear scope (individual activity/process, departmental process, multi departmental

process).

B Responsibilities for tasks, decisions, and results are clearly defined.

B All necessary routine tasks/activities are clearly defined in enough detail to be reproduced consistently.

B How to handle and report exceptions (what-ifs) are defined/covered.

B Decision points, processes, and criteria are identified and defined.

B The process for determining, measuring, and reporting system/procedure performance or

metrics is defined (where needed).

B All related SOPs and systems are listed and integrated where needed.

B Interactions, hand-off documents and/or criteria are defined.

B Interaction responsibilities or decisions are defined.

B Templates, forms, or records for complete documentation are provided or linked.

B Change control system linkage is included where needed.

Implementation and Maintenance Elements

B Enough personnel to execute the activities, decisions, and documentation.

B The appropriate facilities and/or equipment are available.

B Equipment is the right design for the intended use.

B The right tools (hardware, problem solving, etc.) are available. B Personnel training is complete and effective.

B Periodic retraining or reinforcement is conducted.

B The learning capacity or skill level of personnel meets the procedural needs/requirements.

B Procedural communication exists between operators, decision makers, supervisers, and the customer of the output.

B Management/supervision:

B Provides the right environment (physical conditions and working atmosphere).

B Provides enough time or information (planning/scheduling) to complete the procedure.

B Accepts responsibility and accountability for the results.

The master batch record, which provides full details of how a product is to be manufac- tured, could be considered a very important SOP. As with all SOPs, the amount of detail pro- vided should be adequate to assure that different individuals will be consistent in following the process. This not only enhances the potential for consistent product quality, but it also allows more effective evaluation of the causes of any quality deviations and provides a firm basis for process optimization.

The procedures for production and process control are to be reviewed and approved by the quality control unit or more typically QA. This does not mean that QA is to be considered expert in each area of the operation. For example, the production document would normally be reviewed initially by production and/or technical services; the role of QA would be to confirm this review by a responsible person and to further review the document for possible adverse impacts on quality and safety. When reviewing the production and process control documen- tation, it will be essential to check that:

a. The various requirements referenced in the CGMP regulations (especially the other sub-

sections of Subpart F) have been adequately addressed.

b. The documents are in compliance with the relevant sections of any new drug application

(NDA) and approved NDA (ANDA).

c. When applicable, there are appropriate supporting data such as process validation,

analytical method validation, and product stability.

d. The reasons for any proposed changes from previous procedures are clearly defined and

supported.

e. The appropriate functions, such as production and technical services, have been reviewed and signed off.

f. The procedures are compatible with any compendial requirements [such as United States

Pharmacopeia (USP)].

g. The procedure is of the appropriate design and level of definition (refer to SOP consider- ations above).

Having provided written and approved procedures, the next (and more difficult) stage is to ensure that they are followed. This involves training and verification steps. Employees must be given training in all relevant procedures. This should include an understanding and aware- ness of the purpose of the procedures and why they need to be followed. As with all training, it should be confirmed that the employee has actually learned the relevant information and there should be a record of the successful completion of the training (Chap. 3). Next comes the ver- ification step. A combination of some, or preferably all, of the following approaches provides data on compliance.

1. Regular monitoring of compliance by supervisors and managers as they do their daily work. This can be informal but it allows immediate identification and correction of poten- tial compliance problems. It further demonstrates to employees that management does consider compliance to be important.

2. A more systematic review of compliance can also be performed by supervisors and man- agers on a less frequent basis—perhaps monthly. This again would be done by comparing actual activities with written procedures. This more systematic approach ensures that no department, process, or shift is ignored.

3. Quality assurance, along with departmental management, performs an audit of each func- tion. A written report should be issued and if possible any deficiencies should be quantified thereby allowing trends to be monitored. Quantification can be relatively simple, such as classification of deficiencies into critical, major, and minor and recording the number and percentage of each. Alternatively, a numerical weighting system can be used. Manage- ment would be expected to evaluate the audit report, identify the root causes of any noted deficiencies, and to specify appropriate corrective action.

4. Independent audit from outside of the plant adds another level of review. This is similar to three above but may involve personnel from another facility or corporate staff. Also included in this category are regulatory audits such as those by the Food and Drug Admin- istration (FDA). One effective approach to independent audit is to adopt the process assess- ment approach as used by the Malcolm Baldrige National Quality Award. This has the advantages that it can be focused toward specific processes, allows clear identification of causes of deficiencies, gives credit for positive achievement, identifies centers of excellence, and can provide numerical trend data that can stimulate top management to action.

5. The routine quality assurance check of batch records also provides basic information on compliance. This should also be used to review deviation frequency, evaluation, and cor- rective action and to confirm compliance with FDA registration data.

It should be emphasized that if the data generated in 1, 2, and 5 above are used to identify and correct basic problems, then the audits described in 3 and 4 should simply provide confir- mation of compliance. Traditionally, independent audits (4 above) were used to identify areas of noncompliance. Since they are performed relatively infrequently and can only examine small parts of a production operation, they are ineffective as a basis for identifying all noncom- plying activities. The emphasis should be on self-evaluation (1 and 2), which is more likely to be successful than the utilization of a police-type activity. The persistent finding of noncompliance issues by QA should signal that management is not giving enough attention to the subject, that training is not adequate, or that procedures are too complex. QA should then work with the appropriate managers to identify the causes and to initiate corrective action.

In order to encourage self-audit, the FDA had agreed not to ask for copies of internal audit reports (Compliance Policy Guides 7151.02). They may, however, ask for evidence that audits are performed. Also, in the event of litigation requests may be made to see such records.

The computerization of process documentation can improve the effectiveness of compli- ance. The production system can be designed so that one stage has to be completed and any relevant data entered into the computer before the next stage can be initiated. Process control limits can also be included and any atypical results can be made to automatically initiate managerial review. The subject of validation of computer systems is included in Chapter 5.

It would be difficult, if not impossible, to draft an operating procedure that will meet all circumstances. On occasion, deviations from the defined procedure will occur or will be necessary (for example, to evaluate a change). There are usually two types of deviations: planned or unplanned. Planned deviations may be permitted provided there is a planned devi- ation system that allows for the appropriate documentation and approvals (including QA) prior to execution. Unplanned deviations can be accidental or deliberate. In either case, an investigation is typically performed, potential impact on involved batches is deter- mined, and CAPA generated. CAPA could include procedural modification or personnel dis- cipline. Obviously, in an effective compliant operation, deviations should not be a common occurrence.

Section 211.100(a) requires the review and appraisal of changes to production and process control procedures. However, this review and approval should be considered in the broader concept of change control.

CHANGE CONTROL PROCESS

Inputs Activities Output Changes to: Bill of materials Manufacturing process Packaging process Shipping process Product labeling Test methodology Standard operating procedures Registration documents Computer systems Facilities/utilities Equipment New product intro Product discontinuation

Change request initiation (forms and

supporting docs)

#

Request review and approval

#

Change implementation

#

Change results and evaluation

#

Final close out

Request approval

#

Change impact evaluation report

#

Final close out report

A consistent achievement of product quality is dependent on the availability of defined/ approved/validated procedures and the application and adherence to these procedures by trained personnel. In the event that any change is to be introduced into the production oper- ation, it is important to evaluate its potential impact and where necessary provide appropriate evaluation and/or actions. The procedure that controls change is, not unexpectedly, called “change control.” This should be a defined, proactive management system that facilitates a review of any proposed change and monitors the impact of the change. The system should be fail-safe by preventing changes that could adversely affect product quality or conflict with registration or regulatory requirements. The procedure should have identified owner- ship with responsibility for maintenance, monitoring, and improvement of the procedure along with training.

The procedure will involve multiple disciplines including sales and marketing, medical, legal, manufacturing, regulatory affairs, R&D, technical services, and maintenance, as well as QC/QA. Not all functions will need to be involved with all changes. The evaluation of the change, which must be documented, should include the following.

B Clear definition of the proposed change with the reason for the change.

B Identification of potential impact and the evaluations to be performed, such as accelerated stability, revalidation, and retraining.

B Regulatory impact (all countries involved) and approvals required.

B Schedule for implementation.

B Definition of who needs to approve the change and a record of their concurrence.

B Post introduction review to confirm that the change did not have any adverse impact.

The change control procedure is possibly the most important SOP in a plant operation. It is also one of the broadest ranging and most complex. Consequently, the management of the process must be delegated to someone with the necessary knowledge and skills to understand and manage this complexity. In larger facilities, there may be separate change control pro- cedures for different types of change. For example, Labeling, Equipment, Computer Systems, and Procedure/Documents can have individual change control systems but QA

must be involved in oversight and approval and the outcome must be the same-control and management of change.

Evaluation of change control should be part of the routine QA plant audit.

§211.101 CHARGE-IN OF COMPONENTS

Written production and control procedures shall include the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess.

(a) The batch shall be formulated with the intent to provide not less than 100% of the labeled or established amount of active ingredient.

(b) Components for drug product manufacturing shall be weighed, measured, or subdi- vided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information: (1) component name or item code,

(2) receiving or control number,

(3) weight or measure in new container,

(4) batch for which component was dispensed, including its product name, strength, and lot number.

(c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be exam- ined by a second person to assure that:

(1) The component was released by the quality control unit.

(2) The weight or measure is correct as stated in the batch production records. (3) The containers are properly identified.

(d) Each component shall be added to the batch by one person and verified by a second person.

The requirement to “formulate with the intent to provide not less than 100% . . . of the active ingredient” requires some explanation. This certainly makes it unacceptable to add only sufficient material to meet the lower end of the specification, although no reputable manu- facturer would ever use this approach. It is not the intention of the regulations to require cal- culation of an exact amount of active ingredient based on the assay value of the material for each batch of product. Most active ingredients show assay results that are not exactly 100%. With inherent errors in analytical methodology in the order of 1% to 2%, it is not possible to precisely determine the “true” assay value. Consequently, it is acceptable to use material that is within the acceptable specification without specific adjustment to accommodate batch analytical variations. This may not be adequate for materials with a significant, and variable, loss on drying. When it is necessary to calculate a specific quantity, this requirement should be specified in writing by QC or QA and not be the subject of telephone or other verbal com- munication. For a product that is known to show some inherent loss of potency during the pro- duction process, it may be advisable to take the assay value into account for each batch. It may also be necessary to add an overage to allow for this potency loss.

The dispensing step is a critical stage of the manufacturing operation. It ensures that the right amounts of the correct material, released by QC/QA, are allocated to the specified batch of product. The labeling of the component containers [(b)(l)—(4)] makes the later checking at production usage more effective. As written, §211.101(b) could be interpreted that it is only necessary to include the labeling requirements if material is transferred from its original con- tainer. However, such a literal interpretation would be illogical and would weaken the system since the original container will not reference the drug product name, strength, or lot number. The dispensing operation also provides an ideal opportunity to visually examine contain- ers for damage and contents for atypical appearance or foreign matter. Dispensing operators are critical (see Critical Process Parameters, p. 94), and all employees should be made aware of the importance of this step and role.

The requirement that “each container of component dispensed to manufacturing shall be examined by a second person” [§211.101 (c)] is usually interpreted to mean that a second person should be available in the dispensary to perform this duplicate check. Several alterna- tives would also appear to achieve the same result. A single check could be performed in the dispensary with the second independent check being done on receipt by production. With some manual systems, the dispensary label can be removed at the production stage and become part of the batch record. Either routinely, or in the event of a problem, the individual